The present invention relates to solid oral dosage forms containing liquid ingredients, e.g., liquid active agent(s), liquid oral absorption enhancer(s) or liquid solvent(s) for selected drugs, and the processes to prepare them.
It is very difficult to incorporate liquid materials, such as surfactants or oils, for example, polysorbates (Tween 20, 40, 60, 80), polyglycolized glycerides (Labrasol), and vegetable oil, etc., into a solid dosage form, especially a tablet dosage form. Most pharmaceutical carriers cannot carry liquids in the form of a free-flowing powder. When a carrier containing liquid is under load, the liquid will be squeezed out, leading to a reduced compactibility and compressibility of the carrier. Silicas and other ingredients such as microcrystalline cellulose, magnesium oxide, and maltodextrin, can carry liquids in the form of a free-flowing powder. See e.g. U.S. Pat. No. 5,800,834, but these powdered liquids have poor compressibility properties (Spireas, et al, Journal Pharm. Sci. 87 (7): 867 (1998); Spireas, et al, Pharmaceutical Research 4 (10): 1351 (1992); Shah et. al. Drug Development and Industrial Pharmacy 19 (13), 1587 (1993). Liquisolid technology overcomes the limitations of the powdered liquid to form tablets; however, it requires the use of a liquid carrier and a powder coating.
It is an object of the invention to obtain a pharmaceutical composition which comprises a liquid agent in the form of a free-flowing powder which can be encapsulated into hard gelatin capsules, incorporated into tablets or other solid delivery dosage forms.
The present invention relates to an immediate-release pharmaceutical composition comprising a liquid drug, drug solutions, oral absorption enhancer solution or liquid oral absorption enhancers in the form of a free-flowing powder. The free-flowing powders advantageously can be encapsulated into hard gelatin capsules, compressed into tablets, or incorporated into other dosage forms without the aid of a powder coating. Applicants have found that excipients that act as liquid carriers successfully absorb or carry liquid agents and can be compressed into a tablet formulation.
In accordance with an aspect of the present invention, there is provided a solid oral dosage form. The solid oral dosage form comprises a solid carrier containing a liquid. The solid carrier comprises a member selected from the group consisting of magnesium aluminometasilicate, dibasic calcium phosphate, or a combination thereof. The liquid comprises a member selected from the group consisting of a liquid pharmaceutically or biologically active drug or agent, a liquid enhancer, or a combination thereof. The oral dosage form further comprises a solid active a gent wherein the liquid does not include an active agent.
The term xe2x80x9cliquid,xe2x80x9d as used herein, means a liquid at room temperature, or a material that becomes a liquid during processing, especially during a process that requires force or shear, and more specifically, one that forms a tablet.
The term xe2x80x9cliquid active agentxe2x80x9d includes a pharmaceutically or biologically active drug or agent as a liquid or dissolved or dispersed in a liquid.
In general, the liquid is present in the solid oral dosage form in an amount of at least 5 wt. %, preferably in an amount of at least 15 wt. %, based on the total weight of the solid oral dosage form. In general, the liquid is present in the solid oral dosage form in an amount which does not exceed 60 wt. %, and more preferably does not exceed 50 wt. %, and still more preferably does not exceed 35 wt. %.
It has further been found to be of particular advantage that due to the high oil adsorption capacity of these excipients, there is no need for an overcoating, such as silicon dioxide, on the formulation to maintain the free-flow and compression properties.
In one aspect of this invention, the oral dosage form includes absorption enhancers in combination with drugs of low bioavailability (less than approximately 30% bioavailablity). The liquid component may be a mixture with the drug or may be incorporated into a non-drug containing layer, say for example in a multilayer tablet, to minimize degradation caused by intimate contact of drug with the liquid agent.
In one embodiment of this aspect, the carrier of the invention can enhance advantageously the solubility of agents having low water solubility (less than 1.0 mg/ml), for example, corticosteroids which results in lower absorption. The common adverse effect of the long-term therapy of corticosteroids, such as prednisolone, prednisone, is osteoporosis. The use of the granulated dibasic calcium phosphate as a carrier and as a calcium source has significant benefits to minimize the side effect of osteoporosis and to enhance the efficacy of corticosteroids.
In another embodiment of this aspect, the carrier of the invention provides a faster absorption rate of the agent, thereby enhancing the efficacy and reducing or minimizing loss of the agent to pre-systemic metabolism.
In another aspect, the carrier of the invention advantageously can provide a synergistic effect of the active agent. For example, estrogen, especially xcex2-estradiol, undergoes extensive first pass metabolism and requires fast drug input to saturate the enzyme in order to minimize pre-systemic metabolism. In a preferred embodiment of the present invention, the carrier comprising calcium has a synergistic effect on estrogen and it is more effective than estrogen alone at increasing bone mass of the hip and forearm. Thus, the application of liquisolid technology using the granulated dibasic calcium phosphate as a carrier and as a calcium source may increase the benefits of hormone replacement therapy.
In another aspect, the carrier of the present invention may act as a protective agent against gastric irritation caused by some drugs such as ibuprofen and naproxen. The magnesium aluminometasilicate acts as an antacid to provide some protection against the gastric irritation caused by such drugs, in addition to serving as a liquid carrier to achieve a faster absorption.
In a preferred embodiment the solid phase pharmaceutical formulations comprise the carrier spherically granulated dibasic calcium phosphate (Fujicalin, Fuji Chemical Industry Co., Ltd.), or, in an alternative embodiment, magnesium aluminometasilicate (Neusilin, Fuji Chemical Industry Co., Ltd.). Thus in one aspect of the invention these two excipients are used as a carrier for converting liquid drugs, drug solutions into free-flowing powders. For example, magnesium aluminometasilicate and granulated dibasic calcium phosphate may be used as a carrier for a liquid drug, e.g., benzonatate, to provide an alternative dosage form to soft gelatin capsules. In addition, using an antacid, e.g., magnesium aluminometasilicate, may minimize the side effects of gastrointestinal irritation caused by benzonatate.
In another embodiment of this aspect, the carrier can hold, in addition to the enhancers and drugs, agents that inhibit crystal formation.
Agents that inhibit crystal formation of the active pharmaceutical ingredients or absorption enhancers by complexation, surface coating, and/or physical blocking also can be incorporated into the formulation to prevent or slow the rate of crystal propagation. Examples of the agents that inhibit crystal growth of the active pharmaceutical ingredients or absorption enhancers include polyvinylpyrrolidone, polyethylene glycol, cyclodextrins, gelatin, maltodextrin, sorbitol, and polyglyceryl mixed vegetable fatty acid esters.